Alcohol is a widely abused drug and long term, excessive alcohol consumption leads to permanent organ damage or death. Alcoholism results in multiple organ damage and alcohol-induced brain damage is an insidious disease that leads to cognitive deficits in learning and memory. The most damaging pattern of alcohol consumption is episodic or binge drinking (consumption of 4-5 drinks or more per episode) and a high percentage of college students and older adult alcoholics are illustrative of binge drinkers. In order to understand the deleterious consequences of alcoholism, particularly binge type drinking,, and hopefully develop protective therapies, we have been studying a rodent model of alcoholism designed to mimic a single cycle of binge drinking in human alcoholics. Alcohol-induced brain damage has been demonstrated to occur in well-defined populations of neurons in specific brain regions. Binge ethanol consumption in the rodent reduces the ability of the rat to learn new information, similar to memory difficulties seen in humans. Particular regions of the brain that are most sensitive to alcohol toxicity are the entorhinal cortex and the hippocampus, two regions known to be vital for normal memory and cognitive processes. The mechanism underlying ethanol-induced neuronal damage is not well understood, although several explanations have been proposed. Prominent proposals include excitotoxicity associated with excessive glutamate neurotransmitter release, oxidative stress leading to free radical damage and edema related to altered control of ion transport. Neuroprotection or reversal of binge ethanol-induced neurotoxicity in our model was examined with diverse compounds previously shown to be cytoprotective. The nonpsychoactive cannabinoid cannabidiol(CBD), earlier shown to reduce gluteamate toxicity by reducing oxidative stress in cell culture, was evaluated as a a neuroprotectant. When co-administered with ethanol, CBD reduced hippocampal and entorhinal cortical neurodegeneration in a dose-related manner. Supportive of the notion that CBD neuroprotection was due to its antioxidant properties, the common antioxidants butylated hydroxytoluene and alpha-tocopherol provided substantial protection. In contrast, NMDA receptor antagonists, such as dizocilpine and memantine were not neuroprotective. Of the several ion exchange modulators which could counteract alcohol induced edema that leads to cytotoxicity, only furosemide was neuroprotective. It?s interesting to note that furosemide is a potent antioxidant, whereas the non-protective diuretics are not. It would appear that the antioxidant properties of furosemide and not its diuretic properties mediate neuroprotection.. The likelihood that multiple mechanisms mediate alcohol-induced neurotoxicity is high and even the mechanism of alcohol-induced oxidative damage is largely unknown. The search for neuroprotective compounds efficacious in the treatment of alcohol-induced brain damage is ongoing and findings will likely be applicable to the treatment of neurodegenerative diseases, hypoxia and toxin exposure. In addition, a number of endogenous compounds have been shown to be neuroprotective in diverse settings and conditions and protect against oxidative or ethanol insult. For example, pituitary adenylate cyclase-activating polypeptide(PACAP) appears to have both neurotrophic and neuroprotective abilities. Furthermore, the ability of PACAP to reduce alcohol toxicity, which is mimicked by dibutyrl cAMP, suggests this effect is mediated via activation of adenylate cyclase. The development of pharmacotherapeutics that include antioxidant characteristics and anti-inflammatory properties should reduce alcohol-induced cell injury and neurodegeneration.